OXIRACETAM EXERTS NEUROPROTECTIVE EFFECT BY REGULATING NEURONAL APOPTOSIS AND AUTOPHAGY

Chunying Deng^1,2, Wenjing Mao², Peilan Zhang^1*

¹Department of Neurology, Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300350, China - ²Department of Neurology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China

Objective: To explore the neuroprotective effect of oxiracetam by regulating neuronal apoptosis and autophagy.

Methods: Forty-five clean grade healthy male SD rats were randomly divided into a sham operation group, a model group and an oxiracetam group, with 15 rats in each group. The rats in the sham operation group and the model group were given the same dose of normal saline by intraperitoneal gavage. The changes in escape latency, ratio of time spent in the original platform quadrant to the total time and pathological changes to the hippocampus were compared. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 β (IL-1 β), phosphorylated protein kinase B (p-Akt), and phosphorylated rapamycin in the hippocampus were determined. The expression levels of p-mTOR, Bax, Bcl-2, Beclin 1, LC3 Ⅱ/I, and p62 were changed.

Results: Compared with the sham operation group, the escape latency of the model group was significantly prolonged (P<0.05); compared with the model group, the escape latency of the oxiracetam group was shortened on the first day, but there was no significant difference (P>0.05); from the second day, the escape latency of the oxiracetam group was significantly shortened (P<0.05). Compared with the sham operation group, the ratio of residence time in the original platform quadrant to the total time in the model group was significantly decreased, and the expression levels of inflammatory factors, p-Akt, p-mTOR, Beclin 1, LC3 Ⅱ/I, and Bcl-2 in the hippocampus were significantly increased. Meanwhile, the expression levels of Bax and p62 were significantly decreased (P<0.05). In comparison with the model group, the ratio of residence time in the original platform quadrant to the total time in the oxiracetam group was significantly increased; the expression levels of inflammatory factors, p-Akt, p-mTOR, Bcl-2/Bax, and p62 in the hippocampus were significantly increased; and the expression levels of Beclin 1 and LC3 II/I were significantly decreased (P<0.05). In the sham operation group, the hippocampal cells were arranged in an orderly fashion, the nuclear membrane was intact, the nucleolus was clear, and the staining was uniform; conversely, in the model group, the cells were arranged in a disorderly fashion, the number was significantly reduced, and the nucleolus disappeared; and in the oxiracetam group, the number of hippocampal cells was significantly increased and the pathological changes significantly improved in comparison with the model group.

Conclusion: Oxiracetam may activate the PI3K/Akt/mTOR signaling pathway and promote hippocampal neuronal apoptosis and autophagy, inhibiting the inflammatory response of the hippocampal tissue in rats with vascular dementia, improving the pathological changes in the hippocampal tissue, and thus playing a neuroprotective role.